Ashley Krull, Ph.D.
Associate Director
W.W. Williams Cellular Therapy Laboratory
The Ohio State University
Columbus, Ohio, USA
One week ago, a new manuscript re-introduced the concept of CAR-MSCs and piqued the interest of immunologists and cell biologists afresh. The report, published in Nature Biomedical Engineering by Sirpilla et al., comes out of the lab of Dr. Saad Kenderian, M.B., Ch.B., at the Mayo Clinic [1]. The studies used CAR-MSCs to target E-cadherin for the treatment of graph-versus-host disease (GvHD) in immunodeficient mice, positing that enhanced antigen-specific immunosuppression would improve survival outcomes. No doubt more will be said on these cells in an upcoming Under the Microscope feature, but, for now, it’s worth considering the concept and spending some time considering the future applications of this work for cell therapy.
Most, if not all, cell therapy enthusiasts are familiar with MSCs (mesenchymal stromal cells) and the myriad clinical settings in which these cells are being tested. Likewise, everyone knows about CARs (chimeric antigen receptors) and specifically CAR T-cells, six variations of which are now FDA-cleared and commercially available in the United States. But it is likely that far fewer members have thought of combining these acronyms into one, novel product with advantageous properties of each component.
Thankfully, unlike most of us, some researchers have been thinking about utilizing MSCs in the setting of cancer for quite some time. MSCs have been combined with oncolytic viruses for the treatment of ovarian cancer [2]. MSCs have been given alongside CAR T-cells to enhance the cells’ therapeutic efficacy [3]. MSCs have even been transduced with CARs before. For instance, in 2022, Golinelli and colleagues [4], under the leadership of Dr. Massimo Dominici in Moderna, Italy, produced anti-GD2 CAR MSCs that were bi-functional, expressing both tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and the CAR targeting a specific disialoganglioside upregulated in metastatic Ewing’s sarcoma (ES). This approach capitalized on the natural biodistribution of intravenously-injected MSCs to the lungs and liver and, ultimately, provided evidence that the bi-functional MSCs could counteract tumor growth in the lungs of a murine metastatic ES model. But what about needing to home MSCs to cancerous tissues outside of these areas?
Sirpilla et al. approached this problem in the setting of GvHD, wanting to target E-cadherin positive tissues in the colon that are susceptible to attack by immune cells. Would these CAR-MSCs targeting E-cadherin make it to their target the colon? If, and when they locked onto their target, would the heightened immunosuppressive properties of the MSCs be enough to increase survival in the me? According to this latest work, the answer to both questions is yes. The researchers could demonstrate that the CAR-MSCs preferentially homed to the colon and ameliorated the effects of GvHD to promote survival. It is intriguing that the antigen-targeting of MSCs was successful, given that the cells were administered intraperitoneally and not necessarily locally into the colon. Local administration seemed to be the work-around for the MSC biodistribution problem, but if future studies could utilize a simpler injection method while retaining the homing effect of the cells, then undoubtedly many clinicians and patients would favor such an approach.
In thinking about the future of CAR-MSCs, many questions present themselves. Is there a world in which this antigen targeting component removes some trepidation of the FDA when it comes to questions of mechanism of action or potency testing that have long plagued the field? If it can be shown that bringing MSCs into immediate contact with their target and that specific intracellular signaling domains are being utilized to bring about a therapeutic effect, might that be good enough? Could this antigen-targeting approach be utilized for regenerative purposes, potentially homing MSCs to specific sites of damage? The field awaits the answers to these and many other questions as this technology makes its way into Phase I trials.
References
- Sirpilla O, Sakemura RL, Hefazi M, Huynh TN, Can I, Girsch JH, Tapper EE, Cox MJ, Schick KJ, Manriquez-Roman C, Yun K, Stewart CM, Ogbodo EJ, Kimball BL, Mai LK, Gutierrez-Ruiz OL, Rodriguez ML, Gluscevic M, Larson DP, Abel AM, Wierson WA, Olivier G, Siegler EL, Kenderian SS. Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression. Nat Biomed Eng. 2024 Apr 1. doi: 10.1038/s41551-024-01195-6. Epub ahead of print. PMID: 38561490.
- Mader EK, Butler G, Dowdy SC, Mariani A, Knutson KL, Federspiel MJ, Russell SJ, Galanis E, Dietz AB, Peng KW. Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer. J Transl Med. 2013 Jan 24;11:20. doi: 10.1186/1479-5876-11-20. PMID: 23347343; PMCID: PMC3567956.
- McKenna MK, Englisch A, Brenner B, Smith T, Hoyos V, Suzuki M, Brenner MK. Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity. Mol Ther. 2021 May 5;29(5):1808-1820. doi: 10.1016/j.ymthe.2021.02.004. Epub 2021 Feb 9. Erratum in: Mol Ther. 2021 Dec 1;29(12):3529-3533. PMID: 33571680; PMCID: PMC8116608.
- Golinelli G, Grisendi G, Dall'Ora M, Casari G, Spano C, Talami R, Banchelli F, Prapa M, Chiavelli C, Rossignoli F, Candini O, D'Amico R, Nasi M, Cossarizza A, Casarini L, Dominici M. Anti-GD2 CAR MSCs against metastatic Ewing's sarcoma. Transl Oncol. 2022 Jan;15(1):101240. doi: 10.1016/j.tranon.2021.101240. Epub 2021 Oct 12. PMID: 34649148; PMCID: PMC8517927.
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